Coronary artery disease is the world’s deadliest disease. It can cause heart attack or stroke.

Researchers at the School of Medicine have gained important new insights into the development of coronary artery disease, the world’s leading cause of death, in a diverse population that has been previously underrepresented in research studies.

UVA researchers led by Dr. Clint L. Miller and Dr. Chani J. Hodonsky are using a sophisticated new approach to understand how genetic or hereditary factors contribute to the development of coronary artery disease (CAD) in non-adults. I understand how it affects. European. Previous studies have focused primarily on people of European and East Asian descent, limiting generalizability to other ancestry groups or failing to capture the full range of human diversity. This has hindered the detection of heart disease. This new study therefore implements an important new tool to fill gaps in scientific understanding of genetic risk factors in different groups.

UVA researchers say their new approach will help scientists better understand every step of CAD’s development, even before doctors detect it in patients. It could set the stage for new and better ways to treat and possibly prevent CAD.

“This study generates much-needed molecular data from primary vascular tissue derived from ancestrally diverse study participants,” said Miller, of the UVA Center for Public Health Genomics. “By extending these resources to the community, we will be able to better understand the causes of disease progression and begin the search for more targeted treatments for CAD.”

Understanding Coronary Artery Disease

Coronary artery disease is the most common form of heart disease, killing millions of people around the world every year. It is caused by a buildup of fatty plaques in the coronary arteries that supply blood to the heart, eventually blocking blood flow and triggering a stroke or heart attack. Some of this buildup is the result of diet and lifestyle choices, but our genes, the genetic instructions we inherited from our parents, also play a large role in determining our risk.

Previous research has identified hundreds of locations on chromosomes where genetic variations that influence CAD risk exist. But narrowing it down to a specific “culprit” gene — one that scientists believe could help develop treatments — has been difficult. Additionally, Miller and his team wanted to identify genetic variants that specifically affect the heart’s coronary arteries. This is particularly difficult because vascular cells do not always behave the same way in a laboratory dish as they do in a human patient.

Miller’s new approach helps overcome that obstacle, providing researchers with a powerful new workflow for medical research on diverse groups. Using this approach, Miller and his team have already identified a “transcriptional regulatory network” that may shape the strength and maintenance of coronary arteries throughout our lives. Scientists believe that disruption of these networks may play an important role in plaque buildup within arteries and the likelihood of developing CAD.

Additionally, scientists were able to identify specific genes that may be important in the development of plaque buildup in coronary arteries (commonly referred to as “atherosclerosis” or “arteriosclerosis”). Eventually, drugs may be developed that allow doctors to target these genes to treat or prevent plaque buildup. “One of the biggest advantages of population-based genetics research is that the study results are often relevant to a broader patient population than the one shown in the study,” said Dr. Khodonsky said. “Including individuals across the spectrum of genetic ancestry improves our ability to detect these associations and, as a result, to choose which genes to focus on for experimental validation in the laboratory.” We were able to show that there is an increasing amount of evidence available.”

In a new scientific paper, researchers say their comprehensive approach will help overcome obstacles that have limited people’s understanding of coronary artery disease around the world.

“Although these datasets were generated at a bulk level, future studies should profile individual cells and isoforms to resolve in more detail the cellular states involved in CAD risk.” Miller said. “While we are still at the tip of the iceberg in elucidating complex disease mechanisms, we are excited about the continued progress we will make in narrowing the scope of exploration for follow-up preclinical studies.”

Publication of survey results

The researchers published their findings in the scientific journal Cell Genomics. The research team includes: Hodonsky, Adam W. Turner, Mohammad Daoud Khan, Nelson B. Barrientos, Ruben Methorst, Lijan Ma, Nicolas G. López, Jose Verdezoto Mosquera, Gael Auguste, and Emily. Composed of Faber, Wei Feng Ma, Doris Wong, and Suna. Onengut Gumsk, Mariam Kavousi, Patricia A. Peiser, Sander W. van der Laan, Nicholas J. Leeper, Jason C. Kovačić, Johan LM Bjorkegren, Miller. Mr Miller disclosed that he had received funding from biopharmaceutical company AstraZeneca for unrelated work. A complete list of author disclosures is included in the paper.

This research was supported by National Institutes of Health grants R01HL148239, R01HL164577, T32HL007284, R01HL125863, R01HL130423, R01HL135093, and R01HL148167. American Heart Association, grants 20POST35120545, AHA909150, and A14SFRN20840000. Swedish Research Council and Heart and Lung Foundation, grants 2018-02529 and 20170265. Leducq Foundation, “PlaqOmics” grant 18CVD02. and the Single-Cell Data Insights Award from the Chan Zuckerberg Initiative and the Silicon Valley Community Foundation. This research was also supported by fellowship grants from the Bench to Bassinet Pediatric Cardiac Genomics Consortium and the Cardiovascular Development Data Resource Center, and a UVA MSTP training grant (NIH T32GM007267).

UVA’s Department of Biomedical Engineering is a joint program between the School of Medicine and the School of Engineering.

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